Fifty percent of patients with severe congestive heart failure (CHF) die within four years of symptom onset despite optimal therapy. Heart transplantation has an 80% 5-year survival rate, but only 3000 are performed in the US each year, and 5 million patients have CHF. Because the prevalence of CHF is increasing, and the outlook remains dismal, we need new ways to treat CHF. Insulin-like growth factor-I (IGF-I) has pleiotropic effects that may benefit the failing heart. For example, IGF-I, which is activated by growth hormone (GH), is thought to increase cardiac myocyte number and size, stimulate angiogenesis, improve calcium handling and have positive inotropic effects. Despite these putative benefits, no controlled trial of IGF-I/GH protein treatment in clinical CHF has been successful, perhaps due to the relatively short biological half life of IGF-I/GH and insufficient levels in the heart. This limitation, we predict, will be overcome by cardiac gene transfer of IGF-I. Our laboratory has used a variety of cardiac gene transfer methods in preclinical and clinical studies since 1993. In the proposed studies we will: 1) Use a long-term expression vector suitable to treat chronic CHF, which can be easily and efficiently deployed;2) Obtain regulation of gene transcription enabling us to turn on and off transgene expression quickly;3) Activate IGF-I transgene expression in the presence of severe CHF to test efficacy in a stringent manner. The vector that will best fulfill these criteria is the adeno-associated virus (AAV), which provides long-term expression in the heart after intracoronary delivery. The tet-regulation system will provide a suitable means to control transgene expression. Hypothesis. Activation of IGF-I expression will increase function of the failing heart. Aim 1. To evaluate cardiac gene transfer and activation of IGF-I expression in the failing rat heart Aim 1A. Determine efficacy and mechanisms for effects Aim 1B: Survival study Aim 2. To determine if activation of IGF-I expression increases endothelial precursor cell migration to the failing LV Aim 3. To evaluate cardiac gene transfer and activation of IGF-I expression in the failing pig heart Aim 3A. Identify optimal AAV vectors for intracoronary deliver in rats Aim 3B. Confirm optimal AAV vector for intracoronary delivery in pigs Aim 3C. Determine the efficacy and safety of intracoronary AAV.IGFI-tet in pigs with CHF The proposed research is designed to determine the mechanisms by which increased expression of IGF-I has beneficial effects on the failing heart. We also will determine the efficacy and safety of IGF-I gene transfer in rodent and pig models of CHF. Studies have been designed to enable filing an IND application with the FDA during the 5 year tenure of the award, so that clinical trials of IGF-I gene transfer in patients with CHF can be initiated.